Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by destruction of normal epithelial structure, proliferation of fibroblasts, and deposition of connective-tissue matrix proteins. Most patients experience a relentless progression to respiratory failure and death. Recent progress in dissecting key molecular mechanisms involved in disease progression has set the stage for implementation of novel therapies that prevent epithelial cell death, inhibit matrix deposition and deter mesenchymal cell proliferation. We have established with our reported observations and preliminary studies that low concentration inhaled CO provides protection in a murine model of bleomycin-induced lung fibrosis by targeting multiple molecular pathways relevant to the pathogenesis of IPF. Hypothesis: Inhaled low concentration carbon monoxide will slow or arrest the progression of lung fibrosis in patients with IPF. We will test the hypothesis by addressing the following specific aims: Specific Aim #1: To investigate whether, in IPF patients, 3 months of therapy with low dose inhaled CO results in a relative decrease in peripheral blood levels of MMP7 and stability in secondary indicators of disease progression. Specific Aim #2: To investigate the potential role of an IPF specific peripheral blood mononuclear gene expression signature to predict rates of disease progression and determine responsiveness to inhaled CO. Our goal is to study the use of low-dose inhaled CO as a therapeutic agent to treat IPF in humans. For this purpose we have assembled a remarkable group of basic and clinical researchers with expertise in the pathogenesis of IPF, CO biology, biomarker development, large-scale genomics and IPF clinical trials to investigate the effectiveness of a novel inhaled therapy in this devastating disease. Our ancillary proposals will clarify mechanisms of action of CO and validate a peripheral blood genomic signature capable of predicting individual response to CO treatment. The successful completion of this study will provide the basis for the design of a more definitive phase III clinical trial of low dose inhaled CO in IPF. RELEVANCE: This clinical trial will test our hypothesis that low-dose inhaled carbon monoxide will slow disease progression in IPF patients. We have assembled a group of researchers with expertise in the pathogenesis of IPF, CO biology, biomarker development, large-scale genomics and IPF clinical trials to investigate the effectiveness of a novel inhaled therapy in this devastating disease. Successful completion of this study will provide the basis for the design of a more definitive phase III clinical trial of low dose inhaled CO in IPF. (End of Abstract)